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Pathogens (Basel, Switzerland) Dec 2023Surveillance of the renal allograft recipient is essential when monitoring renal function to detect the early onset of rejection and alter therapeutic treatments to...
Surveillance of the renal allograft recipient is essential when monitoring renal function to detect the early onset of rejection and alter therapeutic treatments to treat acute rejection or other causes and improve long-term graft function. If renal function begins to deteriorate, a renal biopsy is often indicated to assess the Banff grade of potential rejection or other causes, especially in the setting of polyoma BK viral load elevation. Although BK infection in the allograft is asymptomatic, reactivation of the virus is known to be associated with the acceleration of pathologic change and a poor outcome in the allograft. BK reactivation in a transplant kidney is not uncommon, and determining inflammation related to the virus versus acute rejection is paramount for appropriate immunosuppressive therapy management. We identified a concomitant polyoma BK virus and West Nile Virus (WNV) infection in two renal transplant patients which, to our knowledge, has not previously been reported. However, other concomitant infections have been reported in renal allografts including BK virus and cytomegalovirus (CMV), CMV and hepatitis C (HCV), and HCV and human immunodeficiency virus (HIV). As WNV has become endemic in many regions of the United States, and since the transmission of the virus via transplanted organs is associated with significant morbidity and mortality, it may be prudent to consider serologic screening for WNV in living donors prior to organ procurement. Regardless, the observation we made and report here should underscore the potential for concomitant viral infections that may be masked when a renal allograft has a significant inflammatory response to BK virus.
PubMed: 38133339
DOI: 10.3390/pathogens12121456 -
Immunity, Inflammation and Disease Aug 2023BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) can cause a significant risk of allograft impairment after kidney transplantation (KT). Intact BKPyV-specific...
INTRODUCTION
BK polyomavirus (BKPyV)-associated nephropathy (BKPyVAN) can cause a significant risk of allograft impairment after kidney transplantation (KT). Intact BKPyV-specific immunity is associated with viral containment. This study investigated BKPyV-specific immunological factors among KT recipients.
METHODS
This prospective study in a single transplant center from January 2019 to August 2019 assessed associations between clinical and immunological characteristics, with a focus on BKPyV-cell-specific immunity and BKPyVAN, among KT recipients aged ≥15 years. The numbers of interferon-gamma (IFN-γ)-producing CD4 T, CD8 T, natural killer (NK), and natural killer T (NKT) cells were measured after stimulation with large T antigen and viral capsid protein 1 (VP1).
RESULTS
In total, 100 KT recipients were included (mean age ± SD, 42 ± 11 years); 35% of the recipients were female patients, and 70% had received induction immunosuppressive therapy. The 1-year cumulative incidence of high-level BKPyV DNAuria (possible BKPyVAN) and (presumptive BKPyVAN) was 18%. Among 40 patients with immunological factor data, pre-KT %NK cells (hazard ratio [HR], 1.258; 95% confidence interval [CI], 1.077-1.469; p = .004) and %VP1-specific NK cells (HR, 1.209; 95% CI, 1.055-1.386; p = .006) were factors independently associated with possible and presumptive BKPyVAN. KT recipients with possible and presumptive BKPyVAN were more likely to exhibit significant mean coefficients of %NK, %VP1-specific NK, and %NKT cells at 1 month after KT than before KT (all p < .05).
CONCLUSION
Individuals with nonspecific and VP1-specific NK cells before KT and increasing numbers of these cells after KT may be at risk for high-level BKPyV DNAuria and presumptive BKPyVAN. Further studies are needed to determine the utility of BKPyV-specific innate immune surveillance in predicting the occurrence of BKPyVAN.
Topics: Humans; Female; Male; Kidney Transplantation; BK Virus; Prospective Studies; Immunosuppressive Agents; Interferon-gamma
PubMed: 37647426
DOI: 10.1002/iid3.956 -
PLoS Pathogens Aug 2023Most humans have a lifelong imperceptible BK Polyomavirus (BKPyV) infection in epithelial cells lining the reno-urinary tract. In kidney transplant recipients,...
Most humans have a lifelong imperceptible BK Polyomavirus (BKPyV) infection in epithelial cells lining the reno-urinary tract. In kidney transplant recipients, unrestricted high-level replication of donor-derived BKPyV in the allograft underlies polyomavirus-associated nephropathy, a condition with massive epithelial cell loss and inflammation causing premature allograft failure. There is limited understanding on how BKPyV disseminates throughout the reno-urinary tract and sometimes causes kidney damage. Tubule epithelial cells are tightly connected and have unique apical and basolateral membrane domains with highly specialized functions but all in vitro BKPyV studies have been performed in non-polarized cells. We therefore generated a polarized cell model of primary renal proximal tubule epithelial cells (RPTECs) and characterized BKPyV entry and release. After 8 days on permeable inserts, RPTECs demonstrated apico-basal polarity. BKPyV entry was most efficient via the apical membrane, that in vivo faces the tubular lumen, and depended on sialic acids. Progeny release started between 48 and 58 hours post-infection (hpi), and was exclusively detected in the apical compartment. From 72 hpi, cell lysis and detachment gradually increased but cells were mainly shed by extrusion and the barrier function was therefore maintained. The decoy-like cells were BKPyV infected and could transmit BKPyV to uninfected cells. By 120 hpi, the epithelial barrier was disrupted by severe cytopathic effects, and BKPyV entered the basolateral compartment mimicking the interstitial space. Addition of BKPyV-specific neutralizing antibodies to this compartment inhibited new infections. Taken together, we propose that during in vivo low-level BKPyV replication, BKPyV disseminates inside the tubular system, thereby causing minimal damage and delaying immune detection. However, in kidney transplant recipients lacking a well-functioning immune system, replication in the allograft will progress and eventually cause denudation of the basement membrane, leading to an increased number of decoy cells, high-level BKPyV-DNAuria and DNAemia, the latter a marker of allograft damage.
Topics: Humans; Cytology; BK Virus; Polyomavirus; Kidney; Epithelial Cells; Polyomavirus Infections
PubMed: 37639485
DOI: 10.1371/journal.ppat.1011622 -
Experimental and Clinical... Oct 2023Nephropathy due to BK virus infection is a major cause of graft dysfunction and loss. No specific treatment has been developed for the BK virus. Here, we compared the... (Randomized Controlled Trial)
Randomized Controlled Trial
Comparative Study of Intravenous Immunoglobulin and Leflunomide Combination Therapy With Intravenous Immunoglobulin Single Therapy in Kidney Transplant Patients With BK Virus Infection: Single-Center Clinical Trial.
OBJECTIVES
Nephropathy due to BK virus infection is a major cause of graft dysfunction and loss. No specific treatment has been developed for the BK virus. Here, we compared the combination of intravenous immunoglobulin and leflunomide versus intravenous immunoglobulin to treat BK virus nephropathy after renal transplant.
MATERIALS AND METHODS
This study was a randomized controlled clinical trial. Sixteen kidney transplant patients with BK virus infection were randomly divided into 2 groups; 1 group received intravenous immunoglobulin, and another group received leflunomide and intravenous immunoglobulin. P < .05 was considered statistically significant.
RESULTS
Results of a polymerase chain reaction test for BK virus after 2 months of treatment were negative in 3 patients in the intravenous immunoglobulin group and in 7 patients in the intravenous immunoglobulin + leflunomide group. The amount of BK virus decreased significantly in each group, and a significant difference was observed between the 2 groups after 3 months (P = .014). The average level of creatinine in the intravenous immunoglobulin group at 1, 2, and 3 months after treatment was 1.7 ± 0.23, 1.8 ± 0.5, and 1.5 ± 0.3, respectively, and in the intravenous immunoglobulin + leflunomide group was 2.1 ± 0.75, 1.76 ± 0.37, and 1.4 ± 0.18, respectively (P > .05).
CONCLUSIONS
Although BK viral load decreased significantly in both groups, there was a significant difference between patients who received intravenous immunoglobulin versus those who received the combination of intravenous immunoglobulin + leflunomide after 3 months. The addition of leflunomide to the intravenous immunoglobulin treatment seems to have a better effect in reducing BK viral load. However, further studies with a larger sample and longer duration are needed.
Topics: Humans; Leflunomide; Kidney Transplantation; Immunoglobulins, Intravenous; Immunosuppressive Agents; Antiviral Agents; Nephritis, Interstitial; Polyomavirus Infections; BK Virus; Tumor Virus Infections
PubMed: 37965956
DOI: 10.6002/ect.2023.0071 -
Plants (Basel, Switzerland) Jan 2024Virus-induced gene silencing (VIGS) is an RNA-mediated reverse genetics technique that has become an effective tool to investigate gene function in plants. Cotton is one... (Review)
Review
Virus-induced gene silencing (VIGS) is an RNA-mediated reverse genetics technique that has become an effective tool to investigate gene function in plants. Cotton is one of the most important economic crops globally. In the past decade, VIGS has been successfully applied in cotton functional genomic studies, including those examining abiotic and biotic stress responses and vegetative and reproductive development. This article summarizes the traditional vectors used in the cotton VIGS system, the visible markers used for endogenous gene silencing, the applications of VIGS in cotton functional genomics, and the limitations of VIGS and how they can be addressed in cotton.
PubMed: 38256825
DOI: 10.3390/plants13020272 -
Journal of Atherosclerosis and... Jul 2023Advances in immunosuppressive therapy; posttransplant management of allograft rejection; and measures against infectious diseases, cardiovascular diseases, and... (Review)
Review
Advances in immunosuppressive therapy; posttransplant management of allograft rejection; and measures against infectious diseases, cardiovascular diseases, and malignancy dramatically improved graft and patient survival after kidney transplantation (KT). Among them, kidney allograft biopsy is an important tool and the gold standard for the diagnosis of various kidney allograft injuries, including allograft rejection, virus-induced nephropathy, calcineurin inhibitor toxicity, and posttransplant glomerular diseases. The Banff Conference on Allograft Pathology has contributed to establishing the diagnostic criteria for kidney allograft rejection and polyomavirus-associated nephropathy that are used as a common standard worldwide. In addition to the for-cause biopsy, many transplant centers perform protocol biopsies in the early and late posttransplant periods to detect and treat allograft injury earlier. Preimplantation biopsy in deceased-donor KT has also been performed, especially in the marginal donor, and attempts have been made to predict the prognosis in combination with clinical information and the renal resistance of hypothermic machine perfusion. Regarding the preimplantation biopsy from a living kidney donor, it can provide useful information on aging and/or early changes in lifestyle diseases, such as glomerulosclerosis, tubulointerstitial changes, and arterial and arteriolar sclerosis, and be used as a reference for the subsequent management of living donors. In this review, morphologic features of important kidney allograft pathology, such as allograft rejection and polyomavirus-associated nephropathy, according to the latest Banff classification and additional information derived from protocol biopsy, and future perspectives with recently developed technologies are discussed.
Topics: Humans; Kidney Transplantation; Graft Rejection; Transplantation, Homologous; Kidney Diseases; Allografts
PubMed: 37245995
DOI: 10.5551/jat.RV22005 -
Cell Host & Microbe Jul 2023Understanding the specificities of human serum antibodies that broadly neutralize HIV can inform prevention and treatment strategies. Here, we describe a deep mutational...
Understanding the specificities of human serum antibodies that broadly neutralize HIV can inform prevention and treatment strategies. Here, we describe a deep mutational scanning system that can measure the effects of combinations of mutations to HIV envelope (Env) on neutralization by antibodies and polyclonal serum. We first show that this system can accurately map how all functionally tolerated mutations to Env affect neutralization by monoclonal antibodies. We then comprehensively map Env mutations that affect neutralization by a set of human polyclonal sera that neutralize diverse strains of HIV and target the site engaging the host receptor CD4. The neutralizing activities of these sera target different epitopes, with most sera having specificities reminiscent of individual characterized monoclonal antibodies, but one serum targeting two epitopes within the CD4-binding site. Mapping the specificity of the neutralizing activity in polyclonal human serum will aid in assessing anti-HIV immune responses to inform prevention strategies.
Topics: Humans; HIV Infections; HIV Antibodies; Antibodies, Neutralizing; Mutation; Epitopes; HIV-1; Antibodies, Monoclonal; HIV Envelope Protein gp120; env Gene Products, Human Immunodeficiency Virus
PubMed: 37327779
DOI: 10.1016/j.chom.2023.05.025 -
The Lancet. Global Health Nov 2023This study assessed the safety and immunogenicity of the Ad26.ZEBOV and MVA-BN-Filo Ebola virus (EBOV) vaccine regimen in infants aged 4-11 months in Guinea and Sierra... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and immunogenicity of the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen in infants: a phase 2, randomised, double-blind, active-controlled trial in Guinea and Sierra Leone.
BACKGROUND
This study assessed the safety and immunogenicity of the Ad26.ZEBOV and MVA-BN-Filo Ebola virus (EBOV) vaccine regimen in infants aged 4-11 months in Guinea and Sierra Leone.
METHODS
In this phase 2, randomised, double-blind, active-controlled trial, we randomly assigned healthy infants (1:1 in a sentinel cohort, 5:2 for the remaining infants via an interactive web response system) to receive Ad26.ZEBOV followed by MVA-BN-Filo (Ebola vaccine group) or two doses of meningococcal quadrivalent conjugate vaccine (control group) administered 56 days apart. Infants were recruited at two sites in west Africa: Conakry, Guinea, and Kambia, Sierra Leone. All infants received the meningococcal vaccine 8 months after being randomly assigned. The primary objective was safety. The secondary objective was immunogenicity, measured as EBOV glycoprotein-binding antibody concentration 21 days post-dose 2, using the Filovirus Animal Non-Clinical Group ELISA. This study is registered with ClinicalTrials.gov (NCT03929757) and the Pan African Clinical Trials Registry (PACTR201905827924069).
FINDINGS
From Aug 20 to Nov 29, 2019, 142 infants were screened and 108 were randomly assigned (Ebola vaccine n=75; control n=33). The most common solicited local adverse event was injection-site pain (Ebola vaccine 15 [20%] of 75; control four [12%] of 33). The most common solicited systemic adverse events with the Ebola vaccine were irritability (26 [35%] of 75), decreased appetite (18 [24%] of 75), pyrexia (16 [21%] of 75), and decreased activity (15 [20%] of 75). In the control group, ten (30%) of 33 had irritability, seven (21%) of 33 had decreased appetite, three (9%) of 33 had pyrexia, and five (15%) of 33 had decreased activity. The frequency of unsolicited adverse events was 83% (62 of 75 infants) in the Ebola vaccine group and 85% (28 of 33 infants) in the control group. No serious adverse events were vaccine-related. In the Ebola vaccine group, EBOV glycoprotein-binding antibody geometric mean concentrations (GMCs) at 21 days post-dose 2 were 27 700 ELISA units (EU)/mL (95% CI 20 477-37 470) in infants aged 4-8 months and 20 481 EU/mL (15 325-27 372) in infants aged 9-11 months. The responder rate was 100% (74 of 74 responded). In the control group, GMCs for both age groups were less than the lower limit of quantification and the responder rate was 3% (one of 33 responded).
INTERPRETATION
Ad26.ZEBOV and MVA-BN-Filo was well tolerated and induced strong humoral responses in infants younger than 1 year. There were no safety concerns related to vaccination.
FUNDING
Janssen Vaccines & Prevention and Innovative Medicines Initiative 2 Joint Undertaking.
TRANSLATION
For the French translation of the abstract see Supplementary Materials section.
Topics: Animals; Humans; Infant; Ebola Vaccines; Hemorrhagic Fever, Ebola; Ebolavirus; Sierra Leone; Guinea; Antibodies, Viral; Double-Blind Method; Glycoproteins; Fever
PubMed: 37858585
DOI: 10.1016/S2214-109X(23)00410-2 -
Scientific Reports Aug 2023BK polyomavirus (BKPyV) is a human DNA virus that resides latent in the host's renal tissue. Reactivation occurs occasionally and in case of kidney transplantation, it...
BK polyomavirus (BKPyV) is a human DNA virus that resides latent in the host's renal tissue. Reactivation occurs occasionally and in case of kidney transplantation, it can lead to polyomavirus-associated nephropathy (PVAN). Due to the lack of specific antivirals for BKPyV and despite the risk of allograft rejection, reduction of immunosuppression remains the main approach for treating PVAN. Current data suggests that mutations can accumulate over time in the major capsid protein VP1 and can lead to neutralization escape in kidney transplant recipients. Herein, we show that mutations occur throughout the entire BKPyV genome, including in VP1. Changes were identified by per-patient comparison of viral genome sequences obtained in samples from 32 kidney recipients with persistent viremia collected at different post-transplant time-points. Amino acid changes were observed in both earlier and later post-transplant samples, although some of them were only found in later samples. Changes in VP1 mainly consisted in the introduction of a new amino acid. A switch back to the conservative amino acid was also observed. This should be considered in future approaches for treating BKPyV infection in kidney transplant recipients.
Topics: Humans; BK Virus; Viremia; Kidney Transplantation; Polyomavirus; Amino Acids
PubMed: 37598256
DOI: 10.1038/s41598-023-40714-4 -
Indian Journal of Pathology &... Nov 2023The incidence of meningoencephalitis (ME) in India is poorly understood, and the exact etiological diagnosis is often not possible. This study was planned to elucidate...
BACKGROUND
The incidence of meningoencephalitis (ME) in India is poorly understood, and the exact etiological diagnosis is often not possible. This study was planned to elucidate the bacterial and viral etiological diagnosis of ME in children less than 5 years of age.
MATERIAL AND METHODS
The present study was conducted in Virus Research and Diagnostic Laboratory (VRDL), Department of Microbiology, King George's Medical University, Lucknow, from July 2020 to June 2022. Serum, cerebrospinal fluid (CSF), and nose/throat swabs were collected from all the enrolled cases of meningoencephalitis in children below 5 years of age and tested for various etiological agents by ELISA and/or real-time PCR.
RESULTS
Of 130 enrolled cases, 50 (38.5%) cases tested positive for one or more etiological agents. Etiological agents of ME detected were Japanese encephalitis virus (JEV) (8.46%), adenovirus (6.92%), influenza virus (5.38%), dengue virus (3.85%), Parvo B-19 virus (3.08%), Orientia tsutsugamushi (3.08%), Herpes Simplex Virus-1 (HSV-1) (1.54%), measles virus (1.54%), and Varicella-Zoster Virus (VZV) (1.54%). Rubella virus, Chikungunya virus (CHKV), Mumps virus, Enteroviruses, Parecho virus, John Cunningham virus (JC), BK virus, Nipah virus, Kyasanur Forest Disease virus (KFD), Chandipura virus, Herpes Simplex Virus (HSV-2), SARS CoV-2, N. Meningitides, and H. Influenzae were tested but not detected in any of the cases.
CONCLUSION
We identified the etiological agents in 50/130 (38.5%) suspected ME cases in children less than 5 years of age, using molecular and ELISA-based diagnostic methods. The four most common pathogens detected were JEV, adenovirus, influenza virus, and dengue virus.
PubMed: 38394398
DOI: 10.4103/ijpm.ijpm_60_23